Male circumcision is performed for cultural, religious and medical reasons with a prevalence of about one third of the world’s male population [1]. The focus on non-medical male circumcision has been gaining momentum in public debate in both Europe and the United States over the past few years. The Danish College of General Practitioners has defined non-medical circumcisions as mutilation [2]. Some Danish medical professionals [3-6], Danish activists [7], and parliament members [8] have promoted the narrative that male circumcision results in decreased penile sensitivity or other types of male sexual dysfunction.

Circumcision carries a risk of complications like any other surgical intervention. Studies from Europe and the United States report overall complication rates of 0.19-3.8% [9]. Complication rates are lower if circumcision is performed during infancy, by experienced providers and under sterile conditions [10]. A Danish study from Rigshospitalet [11] reported an overall complication rate of 5.1% following circumcision in children 0-16 years of age.

Short-term complications comprised superficial skin infections (0.6%), bleeding (1.6%) and anaesthesiology complications (0.6%). Long-term complications included re-operations due to meatal stenosis (0.6%). No major complications such as amputation or death were seen [11]. An age stratification of the data from the Danish study showed lower complication rates in younger boys.

These rates were comparable to the relatively low complication rates previously reported in US studies [12]. The Danish Health Authorities do not recommend a lawenforced ban of non-medical circumcisions in Denmark based on these low rates of short-term complications; however, they do stress the lack of evidence with respect to long-term complications and male sexual function [13].

Inferior sexual function following circumcision is suggested to be caused by loss of sensory tissue followed by keratinisation and desensitisation of the glans penis [14-16]. This hypothesis is generated by two histopathological findings; the description of Meissner’s corpuscles in human prepuce and longer epithelial extensions into underlying connective tissue (rete ridges) in the dorsal glans of the circumcised penis [14, 17].

The purpose of the present study was to test the hypothesis of increased sexual dysfunction in circumcised men through a systematic review of the literature and to perform a detailed synthesis of the available evidence in order to guide patients, parents and decisionmakers on male circumcision.

The objective was to determine if circumcision had an impact on sexual function in males defined as perceived and self-reported erectile dysfunction, pain during intercourse, premature ejaculation, problems in obtaining orgasm, sexual drive, penile sensitivity or sexual satisfaction. A second objective was to determine whether medical circumcision or age at circumcision influenced perceived male sexual function.

METHODS

A protocol including outcomes and overall design was written before searches were performed. Systematic searches were performed in the MEDLINE and EMBASE databases. Exploded index terms (MeSH) were “Circumcision, male” or “Circumcision” in combination with “Sexual dysfunction, physiological”, “Sexual dysfunction, psychological”, “Sexual dysfunction”, “Sexual arousal disorder”, “Premature ejaculation”, “Ejaculation disorder”, “Ejaculation”, “Erectile dysfunction”, “Penile erection”, “Orgasm”, “Orgasm disorder”, “Libido”, “Libido disorder”, “Sensibility” or “Sexual satisfaction”. Keywords were circumcision in combination with sensitivity, sensibility, sensory, neuro*, erectile, ejaculation, orgasm, libido, lust, desire, satisfaction, or sex*. Final searches were performed on 29 February 2016. Additional hand-searches were performed through screening reviews, original studies and their reference lists.

Endnote X7 was used for management of references.

Study selection included a screening of titles and abstracts by the primary author (DMS). Full texts of eligible studies were obtained and screened for the inclusion criteria by two authors independently (SD and DMS). Discrepancies were resolved through discussion until consensus was reached between all three authors.

The following inclusion criteria were applied:

1. Circumcision was the exposure or intervention.

2. Non-exposed controls were either a) uncircumcised participants, b) same participants assessed before circumcision, or c) individuals circumcised at different ages.

3. Outcomes had to include perceived adult male sexual function as defined in the previously mentioned objective. A long-term follow-up period was required.

4. All study designs including a non-exposed control were included. Statistical testing had to be performed in order to compare outcomes of exposed and non-exposed groups. A significance level of p < 0.05 was used to reject the null hypothesis of no difference between exposed and non-exposed participants.

All publication types indexed in databases and all languages were accepted. Chinese studies were translated orally by a fellow PhD student.

Data extraction from studies was performed onto preformatted sheets including the first author’s name, year of publication, country, overall study design, number of participants circumcised and non-circumcised, indication for circumcision, rates for medical and nonmedical circumcisions, age at circumcision, follow-up length, lost to follow-up and age adjustment. Based on the results of statistical testing, outcomes in circumcised males were defined as ”increased”, ”decreased” or ”non-significant”. Erectile dysfunction, pain, premature ejaculation, difficult ejaculation and problems in obtaining orgasm were defined as negative outcomes; and increased levels of sexual drive, penile sensitivity and satisfaction were defined as positive outcomes. If available, estimates adjusted for age were reported. Data extraction was performed by the primary author and reviewed by the co-authors.

The questionnaires used in the identified studies varied with respect to their assessment of ejaculatory function. Some assumptions therefore had to be made for this systematic review. The Brief Male Sexual Functioning Inventory and Male Sexual Health Questionnaire described difficulties in ejaculation, which was included as a separate outcome [18, 19]. The International Index of Erectile Function assessed problems in obtaining an orgasm [20]. The Premature Ejaculation Diagnostic Tool assessed premature ejaculation [21]. Where possible, results from these questionnaires were extracted for each sub-domain of erectile function, ejaculation, drive and satisfaction.

The quality of each study was assessed through levels of evidence for therapy developed by The Oxford Centre for Evidence-based Medicine in 2009 and 2011 [22, 23]. In brief, assessments were performed at the outcome level with the possibility of downgrading if studies failed to measure exposures and outcomes in the same way in both exposed and non-exposed participants, failed to control known confounders, or failed to carry out sufficiently follow-up [22]. A cohort study only assessing sexual function retrospectively was downgraded due to inconsistencies in measuring outcomes and exposure causing recall bias. Both randomized studies and cohort studies were downgraded if the share of patients lost to follow-up exceeded 20% or if loss to follow up was not reported. Age at assessment and medical indication for circumcision were chosen as possible confounders. Sexual difficulties have a rising prevalence with age in men [24] and the indications for circumcision differ with age as well. Studies were downgraded if age was not included in the design through randomisation, through prospective assessments in cohort studies at fixed or short periods of follow-up or through matching. Age could also be included in the analysis through adjustment or stratification. Indication for circumcision was considered mainly medical or nonmedical if reported as such in more than half of the circumcisions performed in the study.

Randomised controlled trials were assessed for random sequence generation, allocation concealment, attrition and blinding of outcome assessment as recommended by the Cochrane Handbook [25]. Blinding of participants or personnel was unfeasible because of the nature of circumcision. If the statistical significance of the intervention and control group had a small absolute effect size, the study was downgraded [23].

Perceived sexual function outcomes in circumcised males was reported overall across studies. Subgroup analyses were performed for circumcised versus uncircumcised males, before versus after circumcision, and both were stratified by medical indication for circumcision.

Evidence for each outcome was summarised as Grade A-D with A indicating the highest level of evidence.

In studies that had the same level of evidence, statistically significant results were given higher priority than nonsignificant results, and inconsistencies between statistically significant results were graded D [22]. Reporting was performed according to the PRISMA statement [26].

The included studies comprised 36 observational studies and two randomised controlled trials. The studies were performed in Asia, The Middle East, North and South America, Europe, Africa and Australia.

Indications for circumcision were mainly non-medical in 11 studies, medical in ten studies and not reported in 17 studies. Age at circumcision was categorised as adulthood or non-infancy in 22 studies, infancy in one study and childhood in three studies (Table 1).

Nine cohort studies had a risk of attrition bias due to insufficient completion of follow-up [28, 31-38], and ten observational studies did not adjust for age [28, 29, 37-44]. A risk of recall bias was present in four retrospective cohort studies [28, 36-38] (Table 1).

The two randomised controlled trials had adequate random sequence generation, allocation concealment [45, 46], and follow-up at one year. No blinding of outcome assessment was performed [47, 48]. One trial was graded down due to a very small absolute effect size, where 98.0-99.4% had a positive sexual function at baseline and an almost equally high sexual function (98.7-99.9%) at follow-up in both arms [47].

A qualitative synthesis without meta-analysis was chosen due to considerable clinical heterogeneity in circumcision indications and procedures, study designs, quality and reporting of results in the identified studies.

Five studies reported adult sexual function outcomes for participants who were circumcised as children or infants compared with participants who were circumcised later in life [29, 40-42, 49]. Four of these did not report indication or adjust for age at assessment [29, 40-42] (Table 1). Circumcision after infancy was associated with nonsignificant differences in satisfaction, increased erection difficulties and decreased premature ejaculation (Grade B). Indication for circumcision after infancy was reported in 49% and the most frequent indication was phimosis [49]. Adult circumcision caused increased pain at intercourse and decreased satisfaction (Grade C) [40]. Circumcision above the age of seven caused increased premature ejaculation (Grade C) [29]. When comparing age groups of 0-12 years or the specific period of 3-6 years at circumcision, non-significant differences were found for erectile dysfunction, premature ejaculation, problems in obtaining orgasm, desire and satisfaction (Grade C) [41, 42].

DISCUSSION

The results of the present systematic review indicate that non-medical circumcision does not generally seem to cause an inferior male sexual function at a statistically significant level (Grade A-B). Following medical circumcisions, erectile dysfunction, pain, difficult ejaculation, drive and sensitivity were all found to be non-significantly changed, whereas premature ejaculation decreased and satisfaction improved (Grade B). However, inconsistencies in reporting of erectile dysfunction (Grade D) were identified in studies with the same level of evidence, and problems in obtaining an orgasm were increased (Grade C). A higher age at circumcision was associated with negative sexual function (Grades B-C).

Studies not reporting indication for circumcision did not reach a high enough level of evidence for assessment of overall sexual function, and some reported inconsistent results when compared with studies of a higher level of evidence. Best level of evidence including randomised controlled trials was identified only for non-medical circumcisions.

Although many of the outcomes of non-medical circumcisions were from one well-designed randomized study, outcomes from lower-quality studies were also consistent with a conclusion of no negative impact on sexual function in circumcised males [48]. Satisfaction was decreased in one randomised study; however, absolute effects were negligible and probably a chance finding due to a type 1 error [47]. Among studies not reporting the indication for circumcision, four were performed in countries where non-medical circumcisions are uncommon and indications were therefore most likely medical [40, 50-52]. Sexual function following medical circumcisions was explored in non-randomised studies only and reported with some inconsistencies. Age at circumcision was only explored in studies including circumcised participants. Optimally, such studies should compare different ages of circumcision to age-matched non-circumcised controls at outcome assessment.

Therefore, studies on medical circumcision and on age at circumcision were more biased than studies about nonmedical circumcisions; and conclusions should accordingly be interpreted with caution. The discrepancy between sexual outcomes following medical and non-medical circumcisions identified in this systematic review has been reported before and it has been suggested that it is confounded by penile pathology causing sexual dysfunction prior to circumcision [49]. Adult medical circumcision is most often performed due to pathological conditions in prepuce, which presumably causes inferior sexual function and mental health disturbances [53-55]. Hence, precircumcision penile pathology may explain the identified discrepancies in obtaining an orgasm when comparing medical and non-medical circumcisions (Table 3) as well as the discrepancies in the results of the many studies not reporting indication when compared with results from studies reporting indication (Table 2 and Table 3).

Therefore, circumcision serves as a proxy for underlying penile pathology, and studies including participants with mainly medical circumcision therefore measure the impact of pathology on sexual function rather than the impact of circumcision. Such selection bias and confounding are best avoided through a randomised design, and future observational studies should at least perform stratification or adjustment for penile pathology. Risks of observer and selective reporting bias were present in the included studies since none had blinded outcome assessment, only half of the studies included validated questionnaires and some studies reported only parts of questionnaires. Health-promoting beliefs related to non-medical circumcisions are present in some cultures [56] and may have caused overestimation of perceived sexual function towards the positive. Other limitations included short follow-up periods of 1-2 years in the prospective studies. Many results were non-significant, possibly due to small sample sizes causing a risk of type II error. Most studies focused on the heterosexual practice of intravaginal intercourse and did not take into account other important heterosexual or homosexual practices that comprise male sexual function.

The strength of this systematic review was the broad search strategy and the inclusion of non-English literature, thereby including participants from all populated continents. The qualitative assessment of the existing literature focused on minimising bias. The stratification by medical indication was performed in order to explore confounding. Other possible confounding factors such as cardiovascular, neurological, and psychiatric co-morbidities, illegal substances, complications to surgery, lifestyle and drugs such as use of psychopharmaceuticals may contribute to an inferior sexual function.

Some of the studies adjusted for these factors; however, many of the factors are age-dependent why adjustment for age at assessment was most important.

The limitation was the inability to perform a meta-analysis.

A pooled analysis could, possibly, have identified more significant associations.

This systematic review focused on the participantcentred sexual function. A number of experimental tudies have investigated male sexual function through objective measures. In circumcised compared with uncircumcised males, differences in sensory tactile thresholds have been found to be non-significant [57-59] and increased [60, 61], and differences in ejaculatory latency period have been found to be non-significant [37, 62,

63] as well as increased [31, 32, 34, 64, 65]. Differences in penile temperature, penilo-cavernous reflexes and penile pudendal-evoked potentials [32, 58, 66] have also been reported. The interpretation of such measures is beyond what is known about male sexual function and these measures were therefore not included in the present systematic review. A recent review with focus on gaps in male circumcision research has specified the needs for consistent objective measures and for correlation of objective to subjective male sexual function outcomes [67]. Other systematic reviews from paediatric societies in the USA and Canada also conclude that circumcision is unlikely to change male sexual function [9, 68].

Medical circumcisions have negative outcomes for obtaining orgasm and discrepancies for erectile dysfunction.

Younger age at circumcision seemed to cause less sexual dysfunction than circumcision later in life. The two latter findings are most likely not causal and more likely biased by observational designs. Future randomized controlled trials of medical circumcisions should be performed. Such studies should include noncircumcised controls and sexual function assessment at entry and at longer-term follow-up beyond two years.

Age at circumcision should be explored in prospective studies including non-circumcised age-matched controls.

The hypothesis of inferior male sexual function following circumcision is not supported by the findings of this systematic review. The popular narrative that male circumcision results in sexual dysfunction does not seem to be supported by evidence.

CONFLICTS OF INTEREST: Disclosure forms provided by the authors are available with the full text of this article at www.danmedj.dk

AC KNOWLEDGEMENTS: We would like to thank PhD student Lin Chia-Hsien from Department of Public Health at the University of Copenhagen for her assistance with the Chinese articles, and Birthe Frimodt-Møller for linguistic assessment.

💬7Comments

Morten Frisch & Brian D. Earp 1. Jul 2016 00:00

In this controversial ‘qualitative synthesis’ paper with numerous methodological shortcomings, Shabanzadeh et al seek to inform the ongoing debate over non-therapeutic childhood male circumcision. However, the authors chose to include any study looking at sexual outcomes after circumcision, whether in boys or adult males, whether in healthy individuals or in patients with a foreskin problem, whether in Africa or in Western settings, and whether with a follow-up period of decades or only a few months to years. Such a cacophony of 38 studies, dominated by findings on short-term sexual consequences of voluntary, adult male circumcision has limited relevance, if any, to the authors’ stated research question: how non-therapeutic circumcision in boys affects the sex lives of the adult men they will one day become.

Editor's note: The full commentary by Frisch and Earp is available as a PDF at the following link:
http://ugeskriftet.dk/files/2016-07-01_commentary_frisch_earp_on_paper_by_shabanzadeh_et_al_dmj_1.pdf

We respectfully disagree that the conductance of systematic reviews is unjustified, and we can only emphasize the importance of identifying all available literature for clarity, before drawing conclusions on a delimited objective, such as, whether the exposure of circumcision has an impact on outcomes of perceived sexual function in adult males. The systematic process was performed according to the PRISMA statement and our conclusion reflected the lack of research in specific domains. We therefore, do not feel the need to justify the methodology any further.
You have problematized that we did not include a Canadian study of sexual partners to circumcised males, however, this was not part of our research objective. To answer the objective of the impact of circumcision on sexual partners perceived sexual function would require yet another systematic review process.

Circumcision is performed on both clinical indications such as penile or prepuce pathology and for non-clinical purposes such as cultural practice or with the aim of HIV-prevention. As we have demonstrated in the paper, many studies fail to distinguish these two populations which is major limitation from a clinical perspective, and one should therefore not draw conclusions about either from such studies. Frisch and Earp suggest that a number of other factors besides this clinical perspective may contribute to the outcome of perceived sexual function in males and we do agree. We have risen the issue of heterogeneity and limitations of the available literature in the discussion.

Our conclusion clearly states the results of the highest quality of available evidence and the lack of high quality studies on consequences of medically indicated circumcision and age at circumcision in order to fully answer our study objectives, and we have specifically stated that a majority of the studies does not take sexual orientation into perspective. We have suggested specific study designs on how to fill the gaps in evidence for future research.
We would like to extend to you both, and all other interested parties, an invitation to collaborate in the future. We can all agree that the field calls for further research, and would be happy to join forces, with contributions from both clinical, epidemiological and physiological angles.

The field of this study is by no means the authors' primary competence. Forthermore the study deals with concepts which are not very well defined.
If you - under such circumstances - out of 3.677 references pick 177 and conclude on only 38 ~ 1 ‰, you may reach EXACTLY the result you are wishing for, whatever it is.
The first requirement of a scientific study is that the study is carried out and described in a way that any scientist would reach the same conclusion if he performed the experiment as described.
I wonder how this highly subjective article passed the peer review?

Response to Dorte Nielsen
Thank you for the interest in our paper.
For how to conduct a systematic review we refer to the PRISMA guidelines. The methodology of the paper has been reported in detail and is reproducible.

We congratulate the authors on their systematic review. They should have been aware of a systematic review in the world's leading specialist journal in this area that concluded male circumcision has no adverse effect on sexual function, sensitivity or sensation (Morris BJ, Krieger JN. Does male circumcision affect sexual function, sensitivity, or satisfaction?--A systematic review. J Sex Med 2013; 10: 2644-2657) and another by Chinese researchers who also performed a meta-analysis of common forms of sexual dysfunction and concluded there was no difference between circumcised and uncircumcised men (Tian Y, Liu W, Wang JZ, Wazir R, Yue X, Wang KJ. Effects of circumcision on male sexual functions: a systematic review and meta-analysis. Asian J Androl 2013; 15: 662-666). Also pertinent to their review is a systematic review of histological correlates that found the foreskin has no role in sexual pleasure (Cox G, Krieger JN, Morris BJ. Histological correlates of penile sexual sensation: Does circumcision make a difference? (Systematic review). Sex Med 2015; 3: 76-85). That study revealed that the neuroreceptors invoked in sexual sensation reside in the glans (head) of the penis.They also seem unaware of a large study in the UK that came to the same conclusions (Homfray V, Tanton C, Mitchell KR, Miller RF, Field N, Macdowall W, Wellings K, Sonnenberg P, Johnson AM, Mercer CH. Examining the association between male circumcision and sexual function: evidence from a British probability survey. AIDS 2015; 29: 1411-1416). Frisch & Earp (Letter above) clearly do not want to accept the scientific evidence. Doing so would undermine their agenda opposing male circumcision.

We did not include all systematic reviews on the subject since the objective was to only include original studies. Due to journal restrictions in maximum numbers of references, we were unable to cite all systematic reviews on the subject in the discussion.

The large observational study from the UK (Homfray et al. 2015) was included in our paper.

We respectfully disagree that the conductance of systematic reviews is unjustified. We can only emphasize the importance of identifying all available literature for clarity, before drawing conclusions on a delimited objective, such as, whether the exposure of circumcision has an impact on outcomes of perceived sexual function in adult males. The systematic process was performed according to the PRISMA statement and our conclusion reflected the lack of research in specific domains. We therefore, do not feel the need to justify the methodology any further.

You have problematized that we did not include a Canadian study of sexual partners to circumcised males, however, this was not part of our research objective. To answer the objective of the impact of circumcision on sexual partners perceived sexual function would require yet another systematic review process.

Circumcision is performed on both clinical indications such as penile or prepuce pathology and for nonclinical purposes such as cultural practice or with the aim of HIV-prevention. As we have demonstrated in the paper, many studies fail to distinguish these two populations which is major limitation from a clinical perspective, and one should therefore not draw conclusions about either from such studies. Frisch and Earp suggest that a number of other factors besides this clinical perspective may contribute to the outcome of perceived sexual function in males and we do agree. We have raised the issue of heterogeneity and limitations of the available literature in the discussion.
Our conclusion clearly states the results of the highest quality of available evidence

[The full response by the Authors is available as a PDF at the following link: http://ugeskriftet.dk/files/response_to_frisch_and_earp_dmj.pdf]